Cancer describes a class of disorders and diseases characterized by the uncontrolled growth of aberrant cells. Currently, cancer is one of the most deadly diseases with about 1.2 million new cases of cancer being diagnosed each year in the United States of America alone.
One form of cancer, accounting for about 3% of all cancers in the United States, is leukemia. This malignant disease is characterized by an abnormal proliferation of white blood cells which can be detected in the peripheral blood and/or bone marrow. Leukemia can be broadly classified into acute and chronic leukemia, which can be subclassified in a variety of ways, including morphology, cytochemistry, cell-surface markers, cytoplasmic markers, cytogenetics and oncogene expression. The most important distinction within acute and chronic leukemia is however between myeloid and lymphoid leukemia.
Acute myeloid leukemia (“AML”) is the most common form of leukemia accounting for about 50% of all leukemia cases and even 85% of all acute leukemia cases involving adults. Conventional methods of treatment for patients diagnosed with AML include chemotherapeutic treatment with a combination of an anthracycline and cytarabine. For patients with AML in whom there is failure to achieve initial remission or in whom there is relapse after chemotherapy, a bone marrow transplantation presently offers the best chance for cure. Because complete remission rates, even after bone marrow transplantation, are low, novel therapies for AML have been developed. These include treatment with immunoconjugates comprising humanized antibodies against CD33 or CD45 conjugated to radioisotopes or drugs. As these immunoconjugates can only induce remission rates in a fraction of the patients suffering from AML, a need still exists for new and improved therapeutic compounds for the treatment of AML. A further disadvantage of the present immunoconjugates is that they contain humanized antibodies. A well known disadvantage of humanized antibodies is that such antibodies still retain some murine sequences and therefore still elicit an unwanted immune reaction, especially when administered for prolonged periods.
Chronic myeloid leukemia (“CML”) has less of an incidence than AML, but still accounts for about 15% of all leukemia cases. Currently, the only unequivocally curative treatment for CML is allogeneic bone marrow transplantation. Unfortunately, for 60% of the patients this therapy may not be available either due to the lack of a suitable donor due to differences in human leukocyte antigens (“HLA”) or the age of the recipient and therefore alternative forms of therapy such as chemotherapy must be employed. Conventional chemotherapy makes use of compounds, such as hydroxyurea, that are cytotoxic for actively dividing cells. Although effective, these agents are not selective for the leukemic clone and this is the cause of undesirable side effects. Moreover, as the disease progresses patients frequently become refractory to chemotherapy. The standard therapy for CML for newly diagnosed patients of CML is considered treatment with interferon such as human leukocyte interferon or recombinant alpha-interferon. A disadvantage of this standard therapy is that patients can become resistant or intolerant to interferon.
Recently, a new compound useful in the treatment of CML has been developed. This compound called imatinib, STI571 or GLEEVEC® is capable of inhibiting Bcr-Abl tyrosine kinase. Disadvantageously, therapy with this compound requires frequent and careful monitoring, particularly for myelosuppression, fluid retention and hepatotoxicity.
A further therapy for CML involves treatment with anti-NCA antibodies (see, US Patent Application No. 2002/0022031). A disadvantage of these antibodies is that the antigen they bind to, i.e., the non-specific cross-reacting antigen (NCA-antigen), is not exclusively expressed on myeloid cells. It can be found on granulocytes as well as on normal colonic mucosa and colonic adenocarcinoma. In view of the drawbacks of the current therapies, there is still a need for new and improved therapeutic compounds for the treatment of CML. In conclusion, there is a need for target molecules and therapeutic compounds specific for myeloid neoplastic diseases such as inter alia AML and CML.
Chinese patent application CN1325874 describes a protein called CLL-1 (C-type lectin like protein) encoded by the mRNA sequence with the Genbank accession number NM 138337. The deduced amino acid sequence of the protein contains 265 amino acids. In CN1325874 is suggested that CLL-1 is a natural killer (NK) cell receptor, i.e., a surface molecule expressed on NK cells, a lymphoid cell type. Furthermore, Northern blot analysis in CN1325874 revealed that CLL-1 is highly expressed in a broad range of tissues and cells, i.e., liver, spleen and peripheral blood cells.